The genetic determinants that regulate the analgesic response to morphine will be studied in purebred and recombinant-inbred strains of mice. The amounts of dopamine, norepinephrine, catecholamine metabolites and tyrosine hydroxylase in different brain regions of selected strains will be examined by high pressure liquid chromatography with an electrochemical detector. Regional assays of narcotic receptors will be carried out in the brains of mouse sublines that differ in their analgesic and running responses to morphine. The mechanism of development of reverse tolerance to the stimulant effects of narcotics will be examined by measuring changes in the number of dopamine receptors in the corpus striatum and nucleus accumbens. The activity of dopamine-sensitive adenylate cyclase in these regions will also be examined. An attempt will be made to define genetic differences in sensitivity to morphine-induced liver damage in mice, and to establish the mechanism responsible for such damage, and its relationship to the metabolism of morphine.